A 5′AMP-activated protein kinase (hereinafter also referred to as AMPK) is a phosphotransferase that is conserved in various living organisms and is involved in energy metabolism of cells, such as uptake of glucose into cells, oxidation of lipids, and generation of glucose transporter 4 (GLUT4) and mitochondria. AMPK is a complex consisting of three subunits of α, β and γ subunits, and is activated through phosphorylation of the 172th threonine of the a subunit by an upstream kinase. The activated AMPK is known to inhibit an anabolic pathway of the metabolism and to accelerate a catabolic pathway corresponding to an energy production pathway.
When AMPK is activated, synthesis of fatty acids, proteins and the like corresponding to the anabolic pathways is inhibited to inhibit cell growth while the energy production pathway of oxidation of fatty acids and glucose transport and like corresponding to the catabolic pathways are accelerated. Accordingly, the activation of AMPK is known to exhibit favorable effects in the prevention/treatment of adult diseases such as diabetes, diabetic complication, lipid metabolism abnormality, non-alcoholic steatohepatitis, arterial sclerosis, obesity and metabolic syndrome, and is recently presumed to exhibit favorable effects in the prevention/treatment of cancers, polycystic kidney, cardiac ischemia, dementia, neurodegenerative diseases, and circadian rhythm sleep disorder (Non Patent Literatures 1 to 3). The activation mechanism of AMPK has, however, not been identified yet.
On the other hand, a prohibitin (hereinafter also referred to as PHB) is a protein highly conserved in plants, fungi, single-cell eukaryotes, animals and the like, and a human PHB is disclosed in, for example, Patent Literature 1. PHB is known to form a cyclic structure constructed by two subunits, that is, prohibitin 1 (hereinafter also referred to as PHB1) and prohibitin 2 (hereinafter also referred to as PHB2). PHB1 and PHB2 together form a complex interdependently, and a deficiency of either PHB1 or PHB2 induces a deficiency of the whole complex formed by these proteins (Non Patent Literatures 4 to 7). While it is reported that PHB is present and functions in a mitochondrial inner membrane, it is also reported that PHB is involved in transcriptional control in a nucleus.
PHB was initially identified as a cell growth inhibition factor. It has been recently revealed, however, that the growth inhibition function is not a function of PHB but derived from a 3′UTR of a PHB gene, and furthermore, it has been revealed that PHB itself rather positively controls cell growth (Non Patent Literatures 8 and 9). Besides, Non Patent Literature 10 describes that a PHB complex is involved in control of lipid metabolism in a nematode to pertain to the lifetime, and Patent Literature 2 describes that PHB2 controls adipose differentiation. The molecular mechanism of PHB involved in these phenomena, however, has not yet been identified.
Besides, Patent Literature 3 discloses a bond between PHB and biguanide, that is, an oral hypoglycemic agent. Furthermore, it is disclosed that the actions of biguanide (namely, activation of AMPK and an ATP lowering action) are inhibited by knockdown of PHB in rat hepatic cells.
The relationship between PHB and AMPK has, however, not been identified yet.